The proposed research will continue ongoing studies investigating the peripheral effects of amphetamine and related drugs on muscle contractions and endurance performance in rats and mice. Treadmill endurance performance is enhanced by low doses of amphetamine, while impaired at high doses. Similarly, nerve-stimulated muscle contractions of the isolated rodent phrenic nerve-diaphragm are enhanced by low concentrations, while concentration-dependent blockade occurs at high drug levels. The proposed studies (classical electrophysiological, twitch, radioenzymatic acetylcholine assay, inhibition of 125 I-alpha-bungarotoxin binding) will be designed to test the hypothesis that enhancement of twitch is caused by amphetamine-stimulated acetylcholine release, while blockcade results from a curare-like block of the postsynaptic nicotinic receptor. Studies will be designed to determine whether tolerance to amphetamine neurotoxicity can be explained by changes in peripheral neuromuscular function and potentially identified by evaluating electrophysiological parameters and/or changes in alpha-bungarotoxin binding. Amphetamine enhances the twitch tension of directly-stimulated muscle contractions (muscles pretreated with alpha-bungarotoxin); high concentrations produce less enhancement. Studies (twitch employing pharmacological antagonists, inhibition of 3H-dihydroalprenolol binding, histofluorescence and radioenzymatic determination of norepinephrine) will be designed to test the hypothesis that enhancement results from amphetamine-stimulated presynaptic norepinephrine release which activates a beta-adrenoceptor on the muscle membrane, while higher amphetamine concentrations cause beta-adrenoceptor blockade. The ability of amphetamine to enhance rat treadmill endurance performance by increasing the availability and/or mobilization of energy substrates (carbohydrates, fats) will be examined. Studies will determine whether tolerance develops to this enhanced performance.